Dietary Inflammatory Index and Head and Neck Cancer: A Multicenter Case-Control Study in Iran

Background: The inflammatory potential of diet may affect carcinogenesis. This study aimed to determine the association between dietary inflammatory index (DII) and the risk of head and neck cancer (HNC), as well as the interaction between DII and cigarette smoking in HNC development within the Iranian population. Study Design: This is a case-control study. Methods: In this multicenter case-control study, participants’ dietary intake was assessed using a validated 130-item food frequency questionnaire, from which DII was computed. The study recruited 876 new cases from referral hospitals across 10 provinces and 3409 healthy controls who were frequency-matched based on age, gender, and residential place. Logistic regression was used to obtain odds ratios (ORs) for HNC across tertiles of DII, which were adjusted for confounding variables. Results: A higher pro-inflammatory diet was associated with an increased risk of all HNC (OR T3 vs. T1 [95% CI]: 1.31 [1.06, 1.62]; P-trend=0.013). There was a significant association between lip and oral cavity cancers and DII (OR T3 vs. T1 [95% CI]: 1.56 [1.16, 1.66]; P-trend=0.004). Furthermore, an inflammatory diet was associated with an increased risk of pharynx cancer (OR T3 vs. T1 [95% CI]: 2.08 [1.14, 3.79]; P-trend=0.02). Additionally, no significant association was observed between DII and larynx cancer, while an interaction was found between DII and tobacco use on the risk of HNC (OR T3 vs. T1 [95% CI]: 2.52 [1.78, 3.57]; P-interaction=0.03). Conclusion: DII was positively associated with HNC risk. There was a significant association between DII and the risk of lip, oral cavity, and pharynx cancers. Additionally, there was an interaction between tobacco use and DII in determining the risk of HNC.

the age-standardized rate rising from 4.8 per 100 000 in 2003 to 8.5 in 2008. 2 Patients with HNC have different complications including, breathing and eating difficulties, and cancer treatment imposes a significant financial burden on patients and their families. 3Therefore, prevention is the best strategy for all people, and identifying the risk factors is vital.
Tobacco (both cigarette and waterpipe) and alcohol consumption are major risk factors for HNC. 4 Other important risk factors include asbestos exposure, human papillomavirus infection, and opium use. 5,6Evidence shows the protective effect of fruits and vegetables against HNC. 4 However, the recent comprehensive review of nutritional factors and cancer risk by the World Cancer Research Fund and the American Cancer Institute concluded that the data on the association between several dietary components with HNC is not convincing. 5hronic inflammation has been recognized as one of the possible mechanisms of carcinogenesis, including HNC. 7 Dietary components have been shown to have anti-inflammatory and pro-inflammatory effects. 8Dietary components such as phenols, antioxidant vitamins, and other nutrients have been associated with the development of several cancers.Some studies have investigated the association between one or several foods or nutrients and cancer risk separately; however, dietary components are consumed together and have synergic or antagonistic interactions.To deal with this, the Dietary Inflammatory Index (DII) was proposed to compute the inflammatory effects of the overall diet. 9Several studies have investigated the association between DII and cancers such as colorectal, breast, prostate, and endometrium. 10,115][16] As such, studies on the association between DII and the risk of HNC, especially in southwestern Asia, are rare.The present study used a large case-control study among the Iranian population to determine the association between DII and the risk of HNC development within the Iranian population.

Participants and study design
The Iranian Study of Opium and Cancer (IROPICAN) is a multicenter case-control study conducted between 2018 to 2020 in referral hospitals affiliated with Universities of Medical Sciences in 10 provinces of Iran, including Sistan and Baluchestan, Kerman, Bushehr, Hormozgan, Khorasan Razavi, Golestan, Mazandaran, Kermanshah, and Tehran. 17We selected cases and controls from the IROPICAN study.There were 876 pathologically confirmed HNC patients who received a cancer diagnosis in less than one year and with no history of any cancers.HNCs in this study were the ICD-O-3 codes of HNC, including the oral, larynx, and pharyngeal cancers (i.e., C00-C09, C11, C12, C14, C31, and C32).
We included 3409 controls who were frequently matched with cases based on age (in 5-year intervals), gender, and residential place.They were selected from hospital visitors who were without cancer, were not family members or friends of the cancer patients, and were visiting the hospital for reasons other than their health complaints.
Participants were asked detailed questions about opium use and its history (e.g., age at initiation, duration, frequency, typical amount, and route), tobacco use (e.g., cigarettes, naswar, chopogh, and waterpipe), history of alcohol consumption, demographic and socioeconomic factors (e.g.age, ethnicity, rural/urban status, education, and occupational history), physical activity (using the validated International Physical Activity Questionnaire, IPAQ 18 ).Information on various aspects of health (personal and family history of cancer) was also obtained.Socioeconomic status (SES) was determined by combining data on education, income, and ownership of some household appliances using principal component analysis.The SES score determined for the control group was used to classify participants into three groups: high, medium, and low social classes.Physical activity workload (PPWL) was estimated based on the job history of participants using the Finland Job Exposure Matrix (FINJEM) 19 .Based on the PPWL scores in control groups, participants were divided into three groups: sedentary (zero PPWL-years), moderate (PPWL-years above zero and less than or equal to 4.80), and heavy (PPWL-years above 4.80).Dental health was assessed by considering decayed, missing, and filled teeth, and participants were divided into three groups based on the scores of the control group.

Assessment of dietary intake and dietary inflammatory index scoring
To assess the dietary intake of participants, we used a validated 130-item food frequency questionnaire (FFQ) which was designed for Persian Cohort Study. 20Cases and controls were asked to answer the FFQ based on their dietary habits one year before cancer diagnosis and one year before the interview, respectively.Total energy and nutrient intake were calculated using the USDA Food Composition Table. 21The DII score was computed based on the method suggested by Shivappa using 38 food parameters, including energy, carbohydrate, fat, protein, fiber, cholesterol, mono-unsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), n-3 fatty acids, n-6 fatty acids, saturated fats (SFAs), trans fat, thiamin, riboflavin, niacin, pyridoxine, folic acid, cobalamin, vitamins A, C, and D, alpha-tocopherol, β-carotene, zinc, selenium, magnesium, iron, caffeine, onion, garlic, black tea, coffee, flavan-3-ol, flavones, flavonols, flavonones, anthocyanidins, and isoflavones. 9Then, the residual method was used to calculate energy-adjusted quantities of all these parameters before analyzing the DII score. 22ietary inflammatory index and head and neck cancer

Statistical analysis
All statistical analyses were performed by Stata software (Stata 14.1, College Station, Texas 77845 USA).Two-sided P values < 0.05 were considered statistically significant.Participants were classified into tertiles of DII scores based on the distribution in the control group.To examine the association between DII and odds of HNC, unconditional logistic regression analysis was used which was controlled for several covariates.The full model was adjusted for energy (kcal/d), age (years), gender (female, male), province (10 provinces), socioeconomic status (low, medium, and high), tobacco use (yes, no), opium use (yes, no), alcohol use (yes, no), dental health (poor, moderate, and good), and physical activity (sedentary, moderate, and high).The trend of odds ratios (ORs) was examined using the median of DII as a continuous variable in the logistic regression models.An interaction term was added to models to analyze the interaction between DII and tobacco or opium use and the risk of HNC.The P value for interactions was estimated by the likelihood ratio test between models with and without the interaction term.We recruited 894 HNC patients from the IROPICAN study and 3483 apparently healthy controls whose data has been used in this study.Participants with unusual energy intake (less than 500 and over 4500 kcal/d) were considered outliers (18 subjects out of 894 patients and 74 subjects out of 3484 controls) and were omitted.

Results
Totally 876 patients and 3409 healthy controls were recruited for the present study.Almost a quarter of the participants in both groups were female (Table 1).Tobacco smoking and opium use were more common among the cases.Regular alcohol use was scarce in both groups.The physical activity status of the participants in both groups was almost similar.Energy and dietary intakes did not significantly differ between patients and controls (Table 2).As observed, the intake of energy, carbohydrate, and trans fatty acids increased from tertile 1 to tertile 3 of DII.However, the intake of vegetables, tomato, garlic, onion, dairy, legumes, and tea decreased.
Table 3 presents the association between DII scores and the risk of all subtypes of HNC and total HNC.After adjusting for confounders, a more pro-inflammatory diet P-trend = 0.004) in the adjusted model.Notably, an inflammatory diet was associated with an increased risk of pharynx cancer even after adjustment for confounders (OR T3 vs.T1: 2.08 [1.14-3.79];P-trend = 0.02).There was no significant association between DII and larynx cancer, and no interaction was seen between DII and opium use.However, an interaction was found between tobacco use and DII on the risk of HNC, meaning that participants who used tobacco and had higher DII scores were at a greater risk of HNC compared to participants who did not

Discussion
This study found that DII is positively associated with HNC risk overall.In addition, there was a significant association between DII and lip and oral cavity cancer and pharynx cancer.However, no significant association was found between DII and larynx cancer.There was an interaction between tobacco use and DII in determining the risk of HNC, whereas no interaction effect was found between opium use and DII.DII is a marker of the pro-inflammatory potential of the diet.Some studies with large sample sizes investigated the association between DII and HNC worldwide, but they are limited, especially in low and middle-income countries. 12,15,16,23,24Our overall findings are consistent with these studies, indicating that a pro-inflammatory diet, as indicated by higher DII scores, is associated with HNC.
Previous studies evaluated the interaction effect of tobacco or smoking with DII on HNC risk, however, but none of them have assessed the interaction between opium use and DII on HNC. 16Shivappa et al reported a positive association between DII and laryngeal cancer in a case-control study in Italy, 25 which is in contrast with our findings.Furthermore, we found a positive significant association between DII and pharynx cancer which is in line with Shivappa's case-control study in Italy. 23Mazul et al reported a significant interaction between smoking, alcohol intake, and DII on HNC risk. 16We assessed opium use in detail, including its interaction effect, finding no interaction effect between opium use and DII on HNC risk.Overall, tobacco use was more prevalent in our population compared to opium use.Moreover, based on the information in Table 1, opium use was not consistent with DII tertiles, indicating that the distribution of opium users in the DII tertiles is not similar.Therefore, we cannot conclude that opium users have a more pro-inflammatory diet.
Evidence suggested that the intake of a diet high in pro-inflammatory parameters accompanied by smoking could exacerbate carcinogenesis.Smoking and alcoholic consumption have been linked with increased oxidative stress. 26,27Smoking-associated oxidative stress activates the inflammatory response pathway, triggering a cascade of events in which the production and release of reactive oxygen species (ROS) at the site of damage and inflammation potentially increase oxidative damage to macromolecular targets, which may lead to cancer initiation and progression. 28he positive association between the DII and HNC might be mediated through the excess production of cytokines such as interleukin-6 (IL-6), IL-8, platelet-derived growth factor, and vascular endothelial growth factor in the tumor microenvironment, which are responsible for carcinogenic activities like anti-apoptosis, tumor angiogenesis, and metastasis. 291][32] Moreover, the direct impact of carbohydrate consumption on the mouth microbiota, leading to increased populations of lactobacilli bacteria, can be another pathway. 3The oral cavity, pharynx, and larynx are all connected anatomical sites, so dysbiosis in one site can lead to dysbiosis in another. 34his study has several strengths.To our knowledge, this is the first large multicenter case-control study in the East Mediterranean region examining the association between DII and the risk of HNC.Additionally, the large sample size allowed us to study the association between DII and overall HNC and its subsites, including oral cavity and larynx cancers.The patients were pathologically confirmed by a pathologist.We also adjusted for several confounding variables, including tobacco, opium, and alcohol use, province, socioeconomic status, dental health, and physical activity.Using a validated FFQ was another strength of the current study. 20owever, this study suffers from some limitations.The lack of an Iranian food composition table is one of the main limitations as food components would differ by country due to environmental and food processing factors.However, using the international food composition table minimizes this problem.[37]

Conclusion
In conclusion, subjects who consumed a pro-inflammatory diet had an increased risk of lip and oral cavity cancer and pharynx cancer compared to those who consumed a low-inflammatory diet in this Iranian population.This is the first study in Iran to examine this association, and the results suggest that increasing the intake of antiinflammatory dietary factors such as plant-based foods rich in fiber and phytochemicals and reducing the intake of pro-inflammatory factors such as fried or processed foods rich in saturated fat or animal protein may be a strategy for reducing the risk of HNC.This can also be the key measure of avoiding tobacco use, indicating that the interaction between a pro-inflammatory diet and tobacco use leads to strikingly higher risks of HNC.• The inflammatory potential of diet may affect carcinogenesis.• In this multicenter case-control study, we assessed dietary inflammatory index (DII) of 876 new cases of head and neck cancer (HNC) and 3409 healthy controls.• DII was positively associated with HNC risk.
• There was an interaction between tobacco use and DII in determining the risk of HNC.

Highlights
Table1.Characteristics of HNC patients and controls participated in the IROPICAN study inIran (2018 and 2020) Note.HNC: Head and neck cancer; DII: Dietary inflammatory index; DMFT: Decayed, missing, or filled teeth.a Dental health was defined by the DMFT score sum of the number of decayed, missing, or filled teeth.there was a significant association between DII and lip and oral cavity cancer (OR [95% CI]: 1.56 [1.16-1.66];

Table 2 .
Energy-adjusted dietary intakes of participants across case (n = 876) and control (n = 3409) groups and tertiles of the dietary inflammatory index (DII) in the IROPICAN study between 2018 and 2020 Dietary inflammatory index and head and neck cancer use tobacco and were in the first tertile (OR T3 vs.T1 [95% CI]: 2.52 [1.78-3.57];P-interaction=0.03, as depicted in Table4).It is worth noting that participants who did not use tobacco or opium but were in the third tertile of DII were still at great risk of HNC (OR T3 vs.T1 [95% CI]: 1.66[1.20-2.29]).

Table 3 .
Odds Ratios and Confidence Intervals for the Association Between DII as Continuous Variable Across Tertiles and HNC by Subtypes in the IROPICAN Study of Iran (2018 and 2020)Note.DII: Dietary inflammatory index; HNC: Head and neck cancer; OR: Odds ratio; CI: Confidence interval; Adjusted for energy (kcal/d), age (years), gender (female, male), province (10 provinces), social economic status (low, medium, and high), tobacco use (yes, no), opium use (yes, no), alcohol use (yes, no), dental health (poor, moderate, and good), and physical activity (sedentary, moderate, and high).The difference in the association between DII and the risk of subtypes of HNC is significant (P of heterogeneity = 0.03).

Table 4 .
Odds Ratios of HNC Stratified by Opium and Tobacco in Relation to DII Treated as Continuous Variable Note.HNC: Head and neck cancer; DII: Dietary inflammatory index; OR: Odds ratio; CI: Confidence interval.